Project Summary/Abstract Continuous, accurate monitoring of cerebral perfusion may reduce morbidity and mortality in patients in critical care. In fact, hypoperfusion and ischemia are leading causes of perioperative stroke in patients undergoing surgical procedures, and secondary brain injury in patients treated in the neuro-intensive care unit. Neurological examination is not feasible in anesthetized patients and is not sufficiently reliable in comatose subjects. While physiology monitoring helps assess the impacts of perfusion changes in the brain, a technology able to directly, continuously and non-invasively monitor cerebral blood flow (CBF) is needed. Diffuse Correlation Spectroscopy (DCS) is an established optical modality which enables non-invasive direct measurements of cerebral blood flow (CBF). As with NIRS, DCS effectiveness on measuring CBF is hampered in the adult population by limited depth penetration and extra-cerebral contamination. With this R21 application we propose to develop a novel approach, called acousto-optic modulation interferometric DCS (AOM iDCS) at 1064 nm which will double brain bold flow sensitivity and specificity. We will first demonstrate enhanced sensitivity to deeper flow by using 1064 nm instead of the typical NIRS wavelengths (680-850 nm). This longer wavelength will allow operation in a considerably lower scattering regime increasing penetration depth and offer an increase in the number of available photons for detection 15-20 times. Because of the inadequate performance of photon counting detectors at wavelengths above 1000 nm, DCS detection will be done using a heterodyne parallel multi-speckle approach. We will then demonstrate acousto-optic photon tagging for homodyne DCS at different depths and establish the theoretical model and analysis procedures to extract BFi of tagged photons. The use of ultrasound plane waves to tag the light field at specific depths will permit separation of cerebral from extra-cerebral blood flow. Finally, we will combine the acousto-optic and interferometric methods in a single prototype, AOM iDCS and refine the theoretical model to extract BFi in the heterodyne mode. The use of an interferometric heterodyne detection technique will permit separation of the light that was frequency shifted by the ultrasound and filtering of higher frequency components resulting from mixing. The synergy of these three advances for DCS, i.e. use of 1064 nm, acousto-optics modulation and heterodyne interferometric detection, will result in a powerful new device with significantly improved performance over current technology. Our team includes leading experts in the field with a proven track record of innovation and clinical translation. We believe the successful realization of this non- invasive cerebral perfusion monitor will successfully translate to the clinic and will have a transformative role in patient management during anesthesia and neuro-critical care.